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Investigating the mechanisms of methotrexate neurotoxicity in patients with childhood leukaemia and long-term survivors.

Forster, Victoria, Carr-Wilkinson, Jane, Tweddle, Deborah A., Nakjang, Sirinita, Choufani, Sanaa, Weksberg, Rosanna and Van Delft, Frederick (2017) Investigating the mechanisms of methotrexate neurotoxicity in patients with childhood leukaemia and long-term survivors. Clinical Lymphoma Myeloma and Leukemia, 17 (2). S385 -S386. ISSN 2152-2650

Item Type: Article

Abstract

Background/Objectives

Adverse neurological events are common (4-20%) during treatment for pediatric acute lymphoblastic leukaemia (ALL) and include seizures, stroke like syndrome and leukoencephalopathy. In addition, chronic neurotoxicity is emerging as a worrying late effect of treatment with long-term survivors experiencing decreased executive function, processing speed and memory function. Survivors are also at increased risk of experiencing learning difficulties, social withdrawal issues and inattention hyperactivity disorders. Methotrexate, an anti-folate chemotherapy agent, is a mainstay of pediatric leukemia treatment regimens globally and is widely implicated as a cause of these neurological side effects. We hypothesise that methotrexate disrupts DNA methylation via effects on S-adenosyl methionine, a key metabolic component that has previously been described to regulate genes involved in myelination.

Design/Methods

Using both the oligodendrocytic-like cell line MO3.13 and glial cells derived from induced pluripotent stem cells (iPSC) treated with methotrexate, we assayed for changes in DNA methylation and effects on gene expression using whole-genome methylation arrays and RNAseq, respectively. Genes with corresponding methylation and expression changes were selected for further studies of expression by real-time qPCR and assessment of protein levels.

Results

We identified DNA methylation and corresponding expression changes in genes involved in neurodevelopmental pathways and neurological disorders. Of particular interest was dose-dependent demethylation and increased gene expression of IRS1, a vital component of insulin signalling pathways that is highly expressed in neural tissue and implicated in regulating cognitive performance. We also detected altered DNA methylation within the PLP1 gene, which encodes the most prevalent protein component of myelin. We found that methotrexate treatment in iPSC-derived oligodendrocytes resulted in increased PLP1 methylation associated with a reduction in PLP1 transcript levels as well as PLP1 protein levels.

Conclusions

Our work provides insight as to the biological mechanisms behind methotrexate-induced neurological side effects for the first time and implicates altered insulin signalling and myelination pathways as a potential causative factor in neurotoxicity. Further work including the use of animal models is warranted for advancing these results towards informing clinical practice.

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More Information

Depositing User: Jane Carr-Wilkinson

Identifiers

Item ID: 10465
Identification Number: https://doi.org/10.1016/j.clml.2017.07.235
ISSN: 2152-2650
URI: http://sure.sunderland.ac.uk/id/eprint/10465
Official URL: https://www.clinical-lymphoma-myeloma-leukemia.com...

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Catalogue record

Date Deposited: 22 Mar 2019 13:48
Last Modified: 18 Dec 2019 16:07

Contributors

Author: Victoria Forster
Author: Jane Carr-Wilkinson
Author: Deborah A. Tweddle
Author: Sirinita Nakjang
Author: Sanaa Choufani
Author: Rosanna Weksberg
Author: Frederick Van Delft

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Nursing and Health Sciences

Subjects

Sciences > Biomedical Sciences
Sciences > Health Sciences

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